Diversified effects of the tumor promoter, TPA, on type IV collagenolytic activity, was observed in fibroblasts at different stages of malignant transformation. Normal human diploid lung fibroblasts were not affected by TPA, but immortalized aneuploid mouse fibroblasts, NIH/3T3, expressed up to 400% increase in type IV collagenolytic activity, and a fibrosarcoma cell line, HTI080 expressed up to 50% increase in the presence of TPA. The collagenolytic activity of the normal fibroblasts was not dependent on the stage of confluency. These results suggest that certain cellular changes, possibly related to the initiation step in the carcinogenic process, are necessary for the induction of type IV collagenolytic activity by the tumor promoter TPA.